tbuckley/cabot-search huggingface dataset:
Sensing Cytosolic DNA Lowers Blood Pressure by Direct cGAMP-Dependent PKGI Activation
Authors: Jie Su, Pierre Coleman, Angeliki Ntorla, Rhys Anderson, Michael J. Shattock, Joseph R. Burgoyne
Journal: Circulation (2023)

BACKGROUND: The major cytosolic DNA sensor cyclic GMP-AMP synthase (cGAS) has emerged as a key mediator of inflammation that underlies cardiovascular disease. On interaction with double-stranded DNA, cGAS generates the second messenger 2′,3′-cyclic GMP-AMP (cGAMP) that directly binds to and activates the stimulator of interferon genes, which in turn leads to enhanced expression of genes encoding interferons and proinflammatory cytokines. Here, we show that cGAMP generated by cGAS also directly activates PKGI (cGMP-dependent protein kinase 1), a mechanism that underlies crosstalk between inflammation and blood pressure regulation. METHODS: The ability of cGAS and cGAMP to activate PKGI was assessed using molecular, cellular, and biochemical analyses, and in myography experiments, as well. The release of cGAMP from the endothelium was measured using an ELISA, and its uptake into the vascular smooth muscle was assessed using molecular and biochemical approaches, including the identification and targeting of specific cGAMP transporters. The blood pressure of wild-type and cGAS –/– mice was assessed using implanted telemetry probes. cGAS was activated by in vivo transfection with G3-YSD or mice were made septic by administration of lipopolysaccharide. RESULTS: The detection of cytosolic DNA by cGAS within the vascular endothelium leads to formation of cGAMP that was found to be actively extruded by MRP1 (multidrug resistance protein 1). Once exported, this cGAMP is then imported into neighboring vascular smooth muscle cells through the volume-regulated anion channel, where it can directly activate PKGI. The activation of PKGI by cGAMP mediates vasorelaxation that is dependent on the activity of MRP1 and volume-regulated anion channel, but independent of the canonical nitric oxide pathway. This mechanism of PKGI activation mediates lowering of blood pressure and contributes to hypotension and tissue hypoperfusion during sepsis. CONCLUSIONS: The activation of PKGI by cGAMP enables the coupling of blood pressure to cytosolic DNA sensing by cGAS, which plays a key role during sepsis by mediating hypotension and tissue hypoperfusion.
Plain Language Formatting of Health Advice Messages May Help to Increase Accessibility and Understanding Through More Elaboration and Processing of the Message
Authors: Lyn M. van Swol, Chen-Ting Chang
Journal: JAMA Pediatrics (2023)

Lisa Stallwood, MSc; Adrian Sammy, BMSc; Matthew Prebeg, BSc; Jacqueline Relihan; Ami Baba, MRes; Rana Charide, MPH; Shahab Sayfi, BSc; Sarah A. Elliott, PhD; Lisa Hartling, PhD; Matthew Munan, MSc; Dawn P. Richards, PhD; Joseph L. Mathew, MD; Tamara Kredo, MBChB, PhD; Lawrence Mbuagbaw, MD, PhD; Ashley Motilall, MPH; Shannon D. Scott, PhD; Miloslav Klugar, PhD; Tamara Lotfi, MD, MPH; Adrienne L. Stevens, PhD; Kevin Pottie, MD; Holger J. Schünemann, MD, PhD; Nancy J. Butcher, PhD; Martin Offringa, MD, PhD; RecMap Members; Lisa Stallwood; Adrian Sammy; Matthew Prebeg; Jacqueline Relihan; Ami Baba; Rana Charide; Shahab Sayfi; Sarah A. Elliott; Lisa Hartling; Matthew Munan; Dawn P. Richards; Joseph L. Mathew; Tamara Kredo; Lawrence Mbuagbaw; Ashley Motilall; Shannon D. Scott; Miloslav Klugar; Tamara Lotfi; Adrienne L. Stevens; Kevin Pottie; Holger J. Schünemann; Nancy J. Butcher; Martin Offringa; Elie A. Akl; Jozef Suvada; Maicon Falavigna
Divergent Actions of Renal Tubular and Endothelial Type 1 IL-1 Receptor Signaling in Toxin-Induced AKI
Authors: Jiafa Ren, Kang Liu, Buyun Wu, Xiaohan Lu, Lianqin Sun, Jamie R. Privratsky, Changying Xing, Matthew J. Robson, Huijuan Mao, Randy D. Blakely, Koki Abe, Tomokazu Souma, Steven D. Crowley
Journal: Journal of the American Society of Nephrology (2023)

Significance Statement Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. However, blockade of IL-1 signaling in AKI has not consistently demonstrated kidney protection. The current murine experiments show that IL-1R1 activation in the proximal tubule exacerbates toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorates AKI by restoring VEGFA-dependent endothelial cell viability. Using this information, future delivery strategies can maximize the protective effects of blocking IL-1R1 while mitigating unwanted actions of IL-1R1 manipulation. Background Activation of the type 1 IL-1 receptor (IL-1R1) triggers a critical innate immune signaling cascade that contributes to the pathogenesis of AKI. IL-1R1 is expressed on some myeloid cell populations and on multiple kidney cell lineages, including tubular and endothelial cells. Pharmacological inhibition of the IL-1R1 does not consistently protect the kidney from injury, suggesting there may be complex, cell-specific effects of IL-1R1 stimulation in AKI. Methods To examine expression of IL-1 and IL-1R1 in intrinsic renal versus infiltrating immune cell populations during AKI, we analyzed single-cell RNA sequencing (scRNA-seq) data from kidney tissues of humans with AKI and mice with acute aristolochic acid exposure. We then investigated cell-specific contributions of renal IL-1R1 signaling to AKI using scRNA-seq, RNA microarray, and pharmacological interventions in mice with IL-1R1 deletion restricted to the proximal tubule or endothelium. Results scRNA-seq analyses demonstrated robust IL-1 expression in myeloid cell populations and low-level IL-1R1 expression in kidney parenchymal cells during toxin-induced AKI. Our genetic studies showed that IL-1R1 activation in the proximal tubule exacerbated toxin-induced AKI and cell death through local suppression of apolipoprotein M. By contrast, IL-1R1 activation in endothelial cells ameliorated aristolochic acid–induced AKI by restoring VEGFA-dependent endothelial cell viability and density. Conclusions These data highlight opposing cell-specific effects of IL-1 receptor signaling on AKI after toxin exposure. Disrupting pathways activated by IL-1R1 in the tubule, while preserving those triggered by IL-1R1 activation on endothelial cells, may afford renoprotection exceeding that of global IL-1R1 inhibition while mitigating unwanted actions of IL-1R1 blockade.
Cox proportional hazards deep neural network identifies peripheral blood complete remission to be at least equivalent to morphologic complete remission in predicting outcomes of patients treated with azacitidine—A prospective cohort study by the <scp>AGMT</scp>
Authors: Lisa Pleyer, Marc Vaisband, Manuel Drost, Michael Pfeilstöcker, Reinhard Stauder, Sonja Heibl, Heinz Sill, Michael Girschikofsky, Margarete Stampfl‐Mattersberger, Angelika Pichler, Bernd Hartmann, Andreas Petzer, Martin Schreder, Clemens A. Schmitt, Sonia Vallet, Thomas Melchardt, Armin Zebisch, Petra Pichler, Nadja Zaborsky, Sigrid Machherndl‐Spandl, Dominik Wolf, Felix Keil, Jan Hasenauer, Julian Larcher‐Senn, Richard Greil
Journal: American Journal of Hematology (2023)

The current gold standard of response assessment in patients with myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), and acute myeloid leukemia (AML) is morphologic complete remission (CR) and CR with incomplete count recovery (CRi), both of which require an invasive BM evaluation. Outside of clinical trials, BM evaluations are only performed in ~50% of patients during follow-up, pinpointing a clinical need for response endpoints that do not necessitate BM assessments. We define and validate a new response type termed "peripheral blood complete remission" (PB-CR) that can be determined from the differential blood count and clinical parameters without necessitating a BM assessment. We compared the predictive value of PB-CR with morphologic CR/CRi in 1441 non-selected, consecutive patients diagnosed with MDS (n = 522; 36.2%), CMML (n = 132; 9.2%), or AML (n = 787; 54.6%), included within the Austrian Myeloid Registry (aMYELOIDr; NCT04438889). Time-to-event analyses were adjusted for 17 covariates remaining in the final Cox proportional hazards (CPH) model. DeepSurv, a CPH neural network model, and permutation-based feature importance were used to validate results. 1441 patients were included. Adjusted median overall survival for patients achieving PB-CR was 22.8 months (95%CI 18.9-26.2) versus 10.4 months (95%CI 9.7-11.2) for those who did not; HR = 0.366 (95%CI 0.303-0.441; p < .0001). Among patients achieving CR, those additionally achieving PB-CR had a median adjusted OS of 32.6 months (95%CI 26.2-49.2) versus 21.7 months (95%CI 16.9-27.7; HR = 0.400 [95%CI 0.190-0.844; p = .0161]) for those who did not. Our deep neural network analysis-based findings from a large, prospective cohort study indicate that BM evaluations solely for the purpose of identifying CR/CRi can be omitted.
β-Amyloid targeting nanodrug for neuron-specific delivery of nucleic acids in Alzheimer's disease mouse models
Authors: Liron L. Israel, Tao Sun, Oliver Braubach, Alysia Cox, Ekaterina S. Shatalova, Harun-Mohammad Rashid, Anna Galstyan, Zachary Grodzinski, Xue Ying Song, Oksana Chepurna, Vladimir A. Ljubimov, Antonella Chiechi, Sachin Sharma, Connor Phebus, Yizhou Wang, Julia Y. Ljubimova, Keith L. Black, Eggehard Holler
Journal: Journal of Controlled Release (2023)

Delivery of therapeutic substances into the brain poses a significant challenge in the treatment of neurological disorders. This is primarily due to the blood-brain barrier (BBB), which restricts access, alongside the limited stability and distribution of these agents within the brain tissue. Here we demonstrate an efficient delivery of microRNA (miRNA) and antisense RNA preferentially to neurons compared to astroglia in the brain of healthy and Alzheimer's disease mice, via disulfide-linked conjugation with poly(ß-L-malic acid-trileucine)-copolymer a biodegradable, amphiphilic, and multivalent platform. By conjugating a D-configured (D3)-peptide (vector) for specific targeting, highly efficient delivery across the BBB is achieved through the Low-Density Lipoprotein Receptor-Related Protein-1 (LRP-1) transcytosis pathway, amyloid beta (Aβ) peptides. Nanodrug distribution was determined by fluorescent labeling and analyzed by microscopy in neurons, astroglia, and in extracellular amyloid plaques typical for Alzheimer's disease. Whereas D-configured BBB-vectors can efficiently target neurons, L-configured (e.g., AP2-peptide) guided vector can only cross BBB but not seem to bind neurons. An analysis of post-injection fluorescence distribution, and RNA-seq followed by real-time PCR validation, confirmed a successful in vivo delivery of morpholino-miRNA-186 nanoconjugates into mouse brain. The size and fluorescence intensity of the intracellular nanodrug particulates were analyzed and verified by a competition with non-fluorescent conjugates. Differentially expressed genes (DEGs) from RNA-seq were identified in the nanodrug injected mice, and the changes of selected DEGs related to Alzheimer's disease were further validated by western blot and real-time PCR. Collectively, these results demonstrated that D3-peptide-conjugated nanopolymer drug is able to achieve neuron-selective delivery of miRNA and can serve as an efficient brain delivery vehicle in Alzheimer's disease (AD) mouse models.
The Genetic, Pharmacogenomic, and Immune Landscapes Associated with Protein Expression across Human Cancers
Authors: Chengxuan Chen, Yuan Liu, Qiang Li, Zhao Zhang, Mei Luo, Yaoming Liu, Leng Han
Journal: Cancer Research (2023)

Abstract Proteomics is a powerful approach that can rapidly enhance our understanding of cancer development. Detailed characterization of the genetic, pharmacogenomic, and immune landscape in relation to protein expression in patients with cancer could provide new insights into the functional roles of proteins in cancer. By taking advantage of the genotype data from The Cancer Genome Atlas and protein expression data from The Cancer Proteome Atlas, we characterized the effects of genetic variants on protein expression across 31 cancer types and identified approximately 100,000 protein quantitative trait loci (pQTL). Among these, over 8000 pQTLs were associated with patient overall survival. Furthermore, characterization of the impact of protein expression on more than 350 imputed anticancer drug responses in patients revealed nearly 230,000 significant associations. In addition, approximately 21,000 significant associations were identified between protein expression and immune cell abundance. Finally, a user-friendly data portal, GPIP (https://hanlaboratory.com/GPIP), was developed featuring multiple modules that enable researchers to explore, visualize, and browse multidimensional data. This detailed analysis reveals the associations between the proteomic landscape and genetic variation, patient outcome, the immune microenvironment, and drug response across cancer types, providing a resource that may offer valuable clinical insights and encourage further functional investigations of proteins in cancer. Significance: Comprehensive characterization of the relationship between protein expression and the genetic, pharmacogenomic, and immune landscape of tumors across cancer types provides a foundation for investigating the role of protein expression in cancer development and treatment.
DNAzyme‐Mediated Cascade Nanoreactor for Cuproptosis‐Promoted Pancreatic Cancer Synergistic Therapy
Authors: Qiao Yu, Jie Zhou, Yong Liu, Xiao Qiong Li, Shan Li, Hong Zhou, Bin Kang, Hong‐Yuan Chen, Jing‐Juan Xu
Journal: Advanced Healthcare Materials (2023)

Abstract Cuproptosis, a kind of newly recognized cell death modality, shows enormous prospect in cancer treatment. The inducer of cuproptosis has more advantages in tumor therapy, especially that can trigger cuproptosis and chemodynamic therapy (CDT) simultaneously. However, cuproptosis is restricted to the deficiency of intracellular copper ions and the nonspecific delivery of copper‐based ionophores. Therefore, high level delivery, responsive release, and utilizing synergistic‐function of inducer become the key on cuproptosis‐based oncotherapy. In this work, a cascade nanosystem is constructed for enhanced cuproptosis and CDT. In the weak acidic environment of tumor cells, DNA, zinc ions, and Cu + can release from the nanosystem. Since Cu + having superior performance in mediating both Fenton‐like reaction and cuproptosis, the released Cu + induces cuproptosis and CDT efficiently, accompanied by Cu 2+ generation. Then Cu 2+ can be converted into Cu + partially by glutathione (GSH) to from a Cu + supply loop and ensure the synergistic action. Meanwhile, the consumption of GSH also contributes to cuproptosis and CDT in return. Finally, DNA and Zn 2+ form DNAzyme to shear catalase‐related RNA, resulting in the accumulation of hydrogen peroxide and further enhancing combination therapy. These results provide a promising nanotherapeutic platform and may inspire the design for potential cancer treatment based on cuproptosis.
Inhibition of METTL3 Results in a Cell-Intrinsic Interferon Response That Enhances Antitumor Immunity
Authors: Andrew A. Guirguis, Yaara Ofir-Rosenfeld, Kathy Knezevic, Wesley Blackaby, David Hardick, Yih-Chih Chan, Ali Motazedian, Andrea Gillespie, Dane Vassiliadis, Enid Y.N. Lam, Kevin Tran, Byron Andrews, Michael E. Harbour, Lina Vasiliauskaite, Claire J. Saunders, Georgia Tsagkogeorga, Aleksandra Azevedo, Joanna Obacz, Ewa S. Pilka, Marie Carkill, Laura MacPherson, Elanor N. Wainwright, Brian Liddicoat, Benjamin J. Blyth, Mark R. Albertella, Oliver Rausch, Mark A. Dawson
Journal: Cancer Discovery (2023)

Abstract Therapies that enhance antitumor immunity have altered the natural history of many cancers. Consequently, leveraging nonoverlapping mechanisms to increase immunogenicity of cancer cells remains a priority. Using a novel enzymatic inhibitor of the RNA methyl­transferase METTL3, we demonstrate a global decrease in N6-methyladenosine (m6A) results in double-stranded RNA (dsRNA) formation and a profound cell-intrinsic interferon response. Through unbiased CRISPR screens, we establish dsRNA-sensing and interferon signaling are primary mediators that potentiate T-cell killing of cancer cells following METTL3 inhibition. We show in a range of immunocompetent mouse models that although METTL3 inhibition is equally efficacious to anti–PD-1 therapy, the combination has far greater preclinical activity. Using SPLINTR barcoding, we demonstrate that anti–PD-1 therapy and METTL3 inhibition target distinct malignant clones, and the combination of these therapies overcomes clones insensitive to the single agents. These data provide the mole­cular and preclinical rationale for employing METTL3 inhibitors to promote antitumor immunity in the clinic. Significance: This work demonstrates that METTL3 inhibition stimulates a cell-intrinsic interferon response through dsRNA formation. This immunomodulatory mechanism is distinct from current immunotherapeutic agents and provides the molecular rationale for combination with anti–PD-1 immune-checkpoint blockade to augment antitumor immunity. This article is featured in Selected Articles from This Issue, p. 2109
Breast Cancer–Secreted Factors Promote Lung Metastasis by Signaling Systemically to Induce a Fibrotic Premetastatic Niche
Authors: Noam Cohen, Dhanashree Mundhe, Sarah K. Deasy, Omer Adler, Nour Ershaid, Tamar Shami, Oshrat Levi-Galibov, Rina Wassermann, Ruth Scherz-Shouval, Neta Erez
Journal: Cancer Research (2023)

Metastatic cancer is largely incurable and is the main cause of cancer-related deaths. The metastatic microenvironment facilitates formation of metastases. Cancer-associated fibroblasts (CAF) are crucial players in generating a hospitable metastatic niche by mediating an inflammatory microenvironment. Fibroblasts also play a central role in modifying the architecture and stiffness of the extracellular matrix (ECM). Resolving the early changes in the metastatic niche could help identify approaches to inhibit metastatic progression. Here, we demonstrate in mouse models of spontaneous breast cancer pulmonary metastasis that fibrotic changes and rewiring of lung fibroblasts occurred at premetastatic stages, suggesting systemic influence by the primary tumor. Activin A (ActA), a TGFβ superfamily member, was secreted from breast tumors and its levels in the blood were highly elevated in tumor-bearing mice. ActA upregulated the expression of profibrotic factors in lung fibroblasts, leading to enhanced collagen deposition in the lung premetastatic niche. ActA signaling was functionally important for lung metastasis, as genetic targeting of ActA in breast cancer cells significantly attenuated lung metastasis and improved survival. Moreover, high levels of ActA in human patients with breast cancer were associated with lung metastatic relapse and poor survival. This study uncovers a novel mechanism by which breast cancer cells systemically rewire the stromal microenvironment in the metastatic niche to facilitate pulmonary metastasis.
Renin–Angiotensin–Aldosterone System Blockade after AKI with or without Recovery among US Veterans with Diabetic Kidney Disease
Authors: Daniel P. Murphy, Julian Wolfson, Scott Reule, Kirsten L. Johansen, Areef Ishani, Paul E. Drawz
Journal: Journal of the American Society of Nephrology (2023)

Among patients with CKD, optimal use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers after AKI is uncertain. Despite these medications' ability to reduce risk of mortality and other adverse outcomes, there is concern that ACEi/ARB use may delay recovery of kidney function or precipitate recurrent AKI. Prior studies have provided conflicting data regarding the optimal timing of these medications after AKI and have not addressed the role of kidney recovery in determining appropriate timing. This study in US Veterans with diabetes mellitus and proteinuria demonstrated an association between ACEi/ARB use and lower mortality. This association was more pronounced with earlier post-AKI ACEi/ARB use and was not meaningfully affected by initiating ACEis/ARBs before versus after recovery from AKI.
Plain Language vs Standard Format for Youth Understanding of COVID-19 Recommendations
Authors: Lisa Stallwood, Adrian Sammy, Matthew Prebeg, Jacqueline Relihan, Ami Baba, Rana Charide, Shahab Sayfi, Sarah A. Elliott, Lisa Hartling, Matthew Munan, Dawn P. Richards, Joseph L. Mathew, Tamara Kredo, Lawrence Mbuagbaw, Ashley Motilall, Shannon D. Scott, Miloslav Klugar, Tamara Lotfi, Adrienne L. Stevens, Kevin Pottie, Holger J. Schünemann, Nancy J. Butcher, Martin Offringa, Lisa Stallwood, Adrian Sammy, Matthew Prebeg, Jacqueline Relihan, Ami Baba, Rana Charide, Shahab Sayfi, Sarah A. Elliott, Lisa Hartling, Matthew Munan, Dawn P. Richards, Joseph L. Mathew, Tamara Kredo, Lawrence Mbuagbaw, Ashley Motilall, Shannon D. Scott, Miloslav Klugar, Tamara Lotfi, Adrienne L. Stevens, Kevin Pottie, Holger J. Schünemann, Nancy J. Butcher, Martin Offringa, Elie A. Akl, Jozef Suvada, Maicon Falavigna
Journal: JAMA Pediatrics (2023)

To ensure that youths can make informed decisions about their health, it is important that health recommendations be presented for understanding by youths.
ECMO PAL: using deep neural networks for survival prediction in venoarterial extracorporeal membrane oxygenation
Authors: Andrew F Stephens, Michael Šeman, Arne Diehl, David Pilcher, Ryan P Barbaro, Daniel Brodie, Vincent Pellegrino, David M Kaye, Shaun D Gregory, Carol Hodgson
Journal: Intensive Care Medicine (2023)

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is a complex and high-risk life support modality used in severe cardiorespiratory failure. ECMO survival scores are used clinically for patient prognostication and outcomes risk adjustment. This study aims to create the first artificial intelligence (AI)-driven ECMO survival score to predict in-hospital mortality based on a large international patient cohort.
Biomimetic Nanophotosensitizer Amplifies Immunogenic Pyroptosis and Triggers Synergistic Cancer Therapy
Authors: Qian Wang, Weiji Qin, Lei Qiao, Min Gao, Man Zhou, Huiru Zhang, Qiuting Sun, Wanqing Yao, Tianhao Yang, Xiaohe Ren, Gengyun Sun, Xiaoyan He
Journal: Advanced Healthcare Materials (2023)

Immunotherapy is considered to be an effective treatment for cancer and has drawn extensive interest. Nevertheless, the insufficient antigenicity and immunosuppressive tumor microenvironment often cause unsatisfactory therapeutic efficacy. Herein, a photo-activated reactive oxygen species (ROS) amplifying system (defined as "M-Cu-T") is developed to induce antitumor immune response by triggering a tumor-specific immunogenic pyroptosis. In M-Cu-T, M1 macrophage membrane-based vesicles are used for drug loading and tumor targeting, photosensitizers (meso-tetra(4-aminophenyl) porphyrin, TAPP) are used as a pyroptosis inducer, copper ions (Cu2+ ) can enhance ROS-induced pyroptosis by consuming antioxidant systems in cells. As expected, the prepared M-Cu-T targets enrichment into tumor cells and cascades the generation of ROS, which further induces pyroptosis through caspase 3-mediated gasdermin E (GSDME) cleavage under laser activation. The pyroptotic cancer cells accompanying secrete related pattern molecules, induce immunogenic cell death, and activate antitumor immunity for immunotherapy. An effective tumor ablation is observed in LLC and CT26 cancer mouse models. This study provides inspiration for boosting the immunogenicity and achieving satisfactory therapeutic effects in cancer therapy.